Radiation-induced fibrosis or scarring is a side-effect of radiation therapy which is characterized by scarring and hardening of tissue inside the body or on the skin. This side-effect can appear in a number of different locations, and may cause additional complications for the patient, depending on where it manifests.
Radiation fibrosis is a significant issue in multiple diseases, most importantly in scarring after radiation treatment for head and neck cancer and breast cancer. Radiation fibrosis refers to a transformation from soft, supple, and pliable soft tissue to one that is stiffer, less flexible, and less able to normally withstand and repair after minor injuries. On the cellular level, radiation induced fibrosis has been linked to abnormal fibroblast activity.
Fibroblasts normally help tissues repair after injury, but in situations of radiation induced fibrosis, these cells overreact, and can produce excessive extracellular matrix or collagen around healthy cells. During radiation the initial inflammation, triggered by therapeutic ionizing radiation, spirals out of control and the inflammatory response turns chronic, with significant resultant scarring.
Radiation changes during treatment may be substantial but the late changes are more debilitating ultimately causing a major decline in quality of life. In head and neck cancer these radiation changes lead to chronic scarring resulting in problems with speech, breathing and swallowing that frequently bring about severe weight loss and sleep apnea. Fibrosis also restricts the range of motion of the neck and certainly leaves chronic cosmetic after effects and injury.
While radiation fibrosis cannot be completely avoided, there are treatments which can be used to manage it, and there are also some steps which can be taken to reduce the risk that it will develop.
It is believed that radiation fibrosis is probably closely linked with lymphedema, which can cause permanent damage to body tissues. Consistent inflammation and irritation often leads to scarring and hardening over time, which in turn makes it more difficult for lymph to circulate, and can cause the lymphedema and fibrosis to spread. Radiation fibrosis can appear weeks or months after radiation therapy, and may grow substantially worse over time.
On skin areas, fibrosis can be a cosmetic issue because it makes the skin look unsightly. In addition, it may restrict freedom of movement because the scarred skin is usually stiff and tough. Radiation fibrosis on the neck, for example, might make it hard for a patient to turn her or his head, because the scarring pulls at the neck. Fibrosis can also occur in internal organs such as the lungs, in which case it may cause secondary complications such as difficulty breathing and susceptibility to infection in the future as a result of the compromised tissue.
Some medications may be helpful for people with radiation fibrosis. In the case of scarring on the skin, gentle stretching, massage, and other exercises can promote freedom of movement or help patients retain their current freedom of movement. Radiation-induced fibrosis inside the body is treated on a case by case basis, depending on the nature of the damage, and medical imaging studies of the involved area may be required in order to develop a treatment plan.
International scientific and medical journals have focused on various formulations for treating fibrosis; representative publications are listed below in chronological order.
Diegelmann, R. F. and Peterkofsky, B. Inhibition of Collagen Secretion from Bone and Cultured Fibroblasts by Microtubular Disruptive Drugs. Proc Natl Acad Sci USA. July 1972; 69 (4):892-896 teaches that colchicine blocks the production and secretion of collagen.
Trnayská, Z., Mikulíková, D., Trnayský, K. discuss “The effects of colchicine and its derivates on the collagen biosynthesis in vitro. Immunosuppression and Inflammation. Agents and Actions. December 1977; 7 (5):563-567.
Lemor, M., de Bustros, S., Glaser, B. M. Low-Dose Colchicine Inhibits Astrocyte, Fibroblast, and Retinal Pigment Epithelial Cell Migration and Proliferation. Archives of Ophthalmology. September 1986; 104 (8):1223-5.
Mansour, M. M., Dunn, M. A., Salah, L. A. Effect of colchicine on collagen synthesis by liver fibroblasts in murine schistosomiasis. Clinica Chimica Acta. September 1988; 177 (1):11-20.
Kershenobich, D., Vargas, F., Garcia-Tsao, G., Perez Tamayo, R., Gent, M., Rojkind, M. Colchicine in the treatment of cirrhosis of the liver. N Engl J Med June 1988; 318:1709-1713 wherein colchicine is used in the treatment of liver cirrhosis, a disease caused by scarring. Despite the chronic use of enterally administered colchicine, there were very few side effects.
Alberts D S, Goldman R, Xu M J, et al. Disposition and metabolism of topically administered alpha-tocopherol acetate: a common ingredient of commercially available sunscreens and cosmetics. Nutr Cancer. 1996; 26 (2):193-201, Vitamin E (tocopherol) is a very common ingredient in sunscreens and cosmetic formulations.
Traber M G, Rallis M, Podda M, Weber C, Maibach H I, Packer L. Penetration and distribution of alpha-tocopherol, alpha- or gamma-tocotrienols applied individually onto murine skin. Lipids. 1998; 33 (1):87-91, teach Vitamin E (tocopherol) levels in the dermis increase greatly after topical application.
Delanian, S. Striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol. Br J Radiol. August 1998; 71 (848):892-4, teach that pentoxifylline, along with tocopherol (Vitamin E) has been used successfully to treat radiation fibrosis. The treatments were not preventive treatments and the formulation was administered orally.
Okunieff, P., Augustine, E., Hicks, J. E., Cornelison, T., Altemus, R., Naydich, B. G. Pentoxifylline in the treatment of radiation-induced fibrosis. Journal of Clinical Oncology. July 2004; 22 (11):2207-13, teach that the single agent, oral pentoxifylline, resulted in significant improvement in late radiation-induced fibrosis. Pentoxifylline is used in topical formulations by Stroud Compounding and Wellness company. Thiele J J, Ekanayake-Mudiyanselage S. Vitamin E in human skin: organ-specific physiology and considerations for its use in dermatology. Mol Aspects Med. 2007; 28 (5-6):646-667, provides evidence that solutions with Vitamin E (tocopherol) concentrations as low as 0.1% can increase Vitamin E levels in the skin.
Burke, Karen E., Chapter 4: Photoprotection of the Skin with Vitamins C and E: Antioxidants and Synergies. Nutrition and Skin: Lessons for Anti-Aging, Beauty and Healthy Skin, Springer Science, 2011: 43-58, teaches that vitamin E absorbs well through the skin and a much higher (11 times more) concentration is achievable by topical administration than with high doses orally. Vitamin E is more protective topically than with oral administration. A composition is provided that maintains stability and delivers active antioxidant to the deep layers of the skin in the d-alpha-tocopherol form, optimally at a concentration of 2-5%.
Nada A, Krishnaiah Y S, Zaghloul A A, Khattab I. In vitro and in vivo Permeation of Vitamin E and Vitamin E Acetate from Cosmetic Formulations. Med Princ Pract. 2011; 20 (6):509-513, teaches and provides further evidence that Vitamin E (tocopherol) is very well absorbed through skin. Vitamin E levels in the dermis increase greatly after topical application.
Lawenda, B. D. Reduce skin fibrosis & possibly breast implant contracture after radiation therapy: vitamin E & pentoxifylline. Integrative Oncology Essential. August 2011, teaches that pentoxifylline is used in the management of peripheral artery disease, leg ulcers, strokes, high-altitude sickness, eye and ear disorders, and sickle cell disease, and diabetic neuropathy. Pentoxifylline, along with tocopherol (vitamin E) has been used to treat radiation fibrosis.
Loiselle, C. Vitamin E, Pentoxifylline, and Radiation Fibrosis. Global Resource for Advancing Cancer Education. November 2011, teaches that during radiation, the inflammation triggered by therapeutic ionizing radiation, spirals out of control and the inflammatory response turns chronic, with significant resultant scarring.
Maduri, S., Atla, V. R. Formulation of colchicine ointment for the treatment of acute gout. Singapore Med J. November 2012; 53 (11):750-4, teaches that colchicine may have adverse effects associated with its administration through the enteral and parenteral routes, but the preparation of dosage forms of colchicine were administered by alternative routes. Based on this study, among the formulations and dosage forms of colchicine, its ointment was a good option available due to its ability to deliver the drug transdermally as well as its ease of preparation and evaluation. Maduri et al. prepared and tested 0.2% and 0.5% colchicine ointments for effectiveness in delivering colchicine transdermally. Colchicine was found to be well-absorbed transdermally for treatment of gout, with no side effects associated with its 0.2% formulation (0.2 gram in 100 ml). 0.2% colchicine achieved the same concentration in the skin as 0.5%. There was no recognition of the use of the colchicine ointment other than for treatment of gout.
Various patents have attempted to solve the problem of radiation-induced fibrosis.
U.S. Pat. No. 5,565,462 to Eitan et al. describes a Composition for Topical Treatment of Psoriasis and Atopic Dermatitis Comprising a Xanthine Derivative. A compound selected from the group of pentoxifylline, propentofylline and torbafylline for improving psoriatic lesions is used topically. The composition uses vitamin A, vitamin D and delta tocopherol for treatment of psoriasis, but does not suggest using the composition of the present invention for treatment and prevention of radiation-induced fibrosis.
U.S. Pat. No. 6,291,516 to Dudek et al. describes Regulators of the Hedgehog Pathway, Compositions and Uses Related Thereto. Treating actinic dermatitis is disclosed. The condition is due to exposure to actinic radiation such as from the sun, ultraviolet waves or x- or gamma radiation and maybe topical formulations when treating epidermal tissue. The composition may include a cAMP inhibitor which may be pentoxifylline and alpha-tocopherol; there is no suggestion or teaching to use the composition of the present invention.
U.S. Pat. No. 6,294,350 to Peterson describes Methods for Treating Fibroproliferative Diseases. Treating radiation induced fibrosis with a cJun antisense compound is disclosed. The composition may comprise pentoxifylline and tocopherol and colchicine; and mixtures thereof. The active components may be delivered transdermally, topically, or by inhalation. A specific formulation for prevention of radiation-induced fibrosis is not provided.
U.S. Pat. No. 7,319,109 to Boggs et al. describes Farnesoid X Receptor Agonists. Compositions specifically prepared for fibrosis caused by radiation are disclosed. Pharmaceutical compositions may be adapted for topical administration and may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. The compositions may include vitamin E. Colchicine is mentioned as an anti-inflammatory substance known for use in treating inflammation that can lead to liver fibrosis.
U.S. Pat. No. 7,705,028 to Caldwell et al. describes a Farnesoid X Receptor Agonists. Pharmaceutical formulations for treating radiation induced liver fibrosis are disclosed. The reference teaches colchicine's known use as a liver fibrosis treating agent.
The formulations may be administered for topical administration as by ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. The formulation includes other therapeutic agents which may be vitamin E.
U.S. Pat. No. 7,863,253 to Jagtap et al. describes Purine Derivatives and Methods of Use Thereof. Purine derivatives and compositions for treating radiation induced injury are disclosed. The formulations may take the form of sprays or topically. Table 2 lists colchicine and colchicine derivatives as antimitotic agents.
U.S. Pat. No. 7,915,225 to Finck describes a Soluble Tumor Necrosis Factor Receptor Treatment of Medical Disorders. Using TNFR:Fc or TNFR:Fc combined with a cytokine used for treating radiation-induced pulmonary fibrosis and to inhibit scarring are disclosed. The composition may further include colchicine and pentoxifylline. The treatment may be a topical preparation; such as, lotions, gels, sprays, ointments. A specific formulation for prevention of radiation-induced fibrosis is not provided.
U.S. Pat. No. 7,998,974 to Milburn et al. describes a Fused Heterocyclic Compounds are disclosed and Their Use as sirtuin Modulators. Sirtuin-modulating compounds which are used in therapeutic treatments increase the life-span of a cell. The compounds may be used in cancer treatment. The treating agents may include pentoxifylline and vitamin E. The treating agent may further include colchicine. The formulation can be lotions, creams or gels. A specific formulation for prevention of radiation-induced fibrosis is not provided.
U.S. Pat. No. 8,058,259 to Thompson et al. describes Substituted 4-{3-[6-Amino-9-(3, 4-Dihydroxy-Tetrahydro-Furan-2-yl)-9h-Purin-2-yl]-prop-2-ynyl}-Piperidine-1-Carboxylic Acid Esters as A2A R Agonists. Purine based compounds used in inflammatory response treatments are disclosed which include dermatitis, eczema, sclerosis and other skin diseases. The compositions may include colchicine and may be topical. A specific formulation for prevention of radiation-induced fibrosis is not provided.
U.S. Pat. No. 9,029,385 to Raghu et al. describes Compositions and Methods for Treating Fibroproliferative Disorders. Radiation-induced, genetic/familial fibrosis treatment compositions are disclosed. The pharmaceutical composition can be in the form of a gel including hydrogel, paste, ointment, cream, spray or lotion. The compositions use pentoxifylline. Table 1, VI uses vitamin E. Colchicine is described as a substance that inhibits fibroblast-like cell proliferation.
U.S. Pat. No. 9,084,746 to Wang et al. describes Therapeutic Applications of Smad7. Smad7 compositions are delivered locally or systemically to a site of inflammation and/or tissue damage for prevention of side effects caused by radiation. The compositions may be applied as creams, salves, ointments, patches, liposomes, nanoparticles, microparticles, timed-release formulations and other materials known in the art for delivery to the oral cavity and/or to the skin. Smad7 compositions comprise tocopherol and pentoxifylline. The reference teaches microtubule inhibitors may be used.
Published Patent Application 2011/0183948 to Levine et al. describes a Treatment of Fibrotic Conditions using Hedgehog Inhibitors. Treating a fibrotic condition due to radiation with a hedgehog inhibitor is disclosed. The composition further contains Vitamin E, pentoxifylline, and colchicine in the treatment of liver fibrosis.
Published Patent Application 2014/0343057 to Palombella et al. describes a Treatment of Lupus, Fibrotic Conditions, and Inflammatory Myopathies and Other Disorders using PI3 Kinase Inhibitors. Topical compositions for treating a radiation fibrotic condition are disclosed. In addition to the PI3 Kinase Inhibitor, the compositions may include vitamin E, pentoxifylline, and colchicine.
Published Patent Application 2015/0335674 to Kottmann et al. describes LDH Inhibitors as Treatment for Fibrosis and Fibrotic-Related Disorders. Treating fibrotic conditions of the lung and other internal organs and tissue due to secondary radiation exposure is disclosed. The treating agents are lactic dehydrogenase inhibitors and may include colchicine, pentoxifylline and tocopherol. The treatment may be applied either transdermal patches, atomizers, or with liposomes. The agents may be used as an aerosol.
As shown in the prior art, fibrotic conditions were treated with specially prepared or synthesized organic compounds, such as, xanthine derivatives, hedgehog inhibitors, cJun antisense compounds, Farnesoid X Receptor agonists, purine derivatives, sirtuin-modulating compounds, Smad7 compositions, PI3 Kinase inhibitors and the like. Often these specially prepared organic compounds, referred to as pharmaceutical compositions or drugs are combined with pentoxifylline, tocopherol (Vitamin E), or colchicine. There is no teaching, suggestion or disclosure that colchicine alone or in combination with pentoxifylline and tocopherol (Vitamin E) could be used as a topical transdermal treatment to prevent or relieve the damaging or injurious effect of radiation-induced fibrosis.